Substituted piperidines

ABSTRACT

A novel class of substituted piperidines, pharmaceutical compositions comprising them and use thereof in the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor. More particularly, the compounds are useful for the treatment and/or prevention of diseases and disorders in which an interaction with the histamine H3 receptor is beneficial.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/245,236 filed on Sep. 12, 2002 and claims priority under 35 U.S.C.119 of Danish application no. PA 2001 01344 filed Sep. 14, 2001 and U.S.provisional application No. 60/323,004 filed Sep. 18, 2001, the contentsof which are fully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel substituted piperidines, to theuse of these compounds as pharmaceutical compositions, to pharmaceuticalcompositions comprising the compounds, and to a method of treatmentemploying these compounds and compositions. The present compounds show ahigh and selective binding affinity to the histamine H3 receptorindicating histamine H3 receptor antagonistic, inverse agonistic oragonistic activity. As a result, the compounds are useful for thetreatment and/or prevention of diseases and disorders related to thehistamine H3 receptor.

BACKGROUND OF THE INVENTION

The existence of the histamine H3 receptor has been known for severalyears and the receptor is of current interest for the development of newmedicaments (see eg Stark, H.; Schlicker, E.; Schunack, W., Drugs Fut.1996, 21, 507-520; Leurs, R.; Timmerman, H.; Vollinga, R. C., Progressin Drug Research 1995, 45, 107-165). Recently, the human histamine H3receptor has been cloned, of Lovenberg, T. W. et al., MolecularPharmacology, June 1999, 55, 1101-1107. The histamine H3 receptor is apresynaptic autoreceptor located both in the central and the peripheralnervous system, the skin and in organs such as the lung, the intestine,probably the spleen and the gastrointestinal tract. Recent evidencesuggests that the H3 receptor show intrinsic, constitutive activity, invitro as well as in vivo (ie it is active in the absence of an agonist;see eg Morisset et al., Nature 2000, 408, 860-864). Compounds acting asinverse agonists can inhibit this activity. The histamine H3 receptorhas been demonstrated to regulate the release of histamine and also ofother neurotransmitters such as serotonin and acetylcholine. A histamineH3 receptor antagonist or inverse agonist would therefore be expected toincrease the release of these neurotransmitters in the brain. Ahistamine H3 receptor agonist, on the contrary, leads to an inhibitionof the biosynthesis of histamine and an inhibition of the release ofhistamine and also of other neurotransmitters such as serotonin andacetylcholine. These findings suggest that histamine H3 receptoragonists, inverse agonists and antagonists could be important mediatorsof neuronal activity. Accordingly, the histamine H3 receptor is animportant target for new therapeutics.

Piperidines similar to the compounds of the present invention havepreviously been prepared, and their biological properties have beeninvestigated, cf U.S. Pat. No. 3,577,440, WO 01/44191, J. Comb. Chemical(2000), 2(3), 266-275, WO 96/29307, WO 95/00512 and GB 2000136.

However, these references neither disclose nor suggest that thesesubstituted piperidines may have a histamine H3 receptor antagonistic oragonistic activity.

Several publications disclose the preparation and use of histamine H3agonists and antagonists. Most of these are imidazole derivatives (seeeg Stark et al., Drugs of the Future 1996, 21, 507-520; Tozer,Kalinddjian, Expert Opinion on Therapeutic Patents, 2000, 10,1045-1055). However, recently some imidazole-free ligands of the rathistamine H3 receptor have been described. Thus, Walczynski et al.(Arch. Pharm. Pharm. Med. Chem. 1999, 332, 389-398), Linney et al. (J.Med. Chem. 2000, 43, 2362-2370), Ganellin et al. (Arch. Pharm. Pharm.Med. Chem. 1998, 331, 395-404), Walczynski et al. (II Farmaco 1999, 54,684-694), Kalindjian et al. (WO 99/42458), Schwartz et al. (EP 0 978512), and Ludwig et al. (WO 97/17345) disclose cyclic amines having rathistamine H3 receptor agonistic or antagonistic activity. However, thestructures of these amines are quite different from that of the presentcompounds. Thus, none of the amines disclosed in these publicationscontain a piperidine structure, as is the case in the present compounds.

In view of the art's interest in histamine H3 receptor agonists, inverseagonists and antagonists, novel compounds which interact with thehistamine H3 receptor would be a highly desirable contribution to theart. The present invention provides such a contribution to the art beingbased on the finding that a novel class of substituted piperidines has ahigh and specific affinity to the histamine H3 receptor.

Due to their interaction with the histamine H3 receptor, the presentcompounds are useful in the treatment and/or prevention of a wide rangeof conditions and disorders in which an interaction with the histamineH3 receptor is beneficial. Thus, the compounds may find use eg in thetreatment of diseases of the central nervous system, the peripheralnervous system, the cardiovascular system, the pulmonary system, thegastrointestinal system and the endocrinological system.

DEFINITIONS

In the structural formulae given herein and throughout the presentspecification, the following terms have the indicated meaning:

The term “halogen” means F, Cl, Br or I.

The term “C₁₋₆-alkyl” as used herein represent a branched or straighthydrocarbon group having from 1 to 6 carbon atoms. Typical C₁₋₆-alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, isohexyl and the like.

The term “C₂₋₆-alkenyl” as used herein represents a branched or straighthydrocarbon group having from 2 to 6 carbon atoms and at least onedouble bond. Examples of such groups include, but are not limited to,ethenyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-butadienyl,1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl andthe like.

The term “C₂₋₆-alkynyl” as used herein represents a branched or straighthydrocarbon group having from 2 to 6 carbon atoms and at least onetriple bond. Examples of such groups include, but are not limited to,ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl,2-pentynyl, 1hexynyl, 2-hexynyl and the like.

The term “C₁₋₆-alkoxy” as used herein, alone or in combination, refersto the radical —O—C₁₋₆-alkyl wherein C₁₋₆-alkyl is as defined above.Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy,butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxyand the like.

The term “C₁₋₆-alkylthio” as used herein, alone or in combination,refers to the radical —S—C₁₋₆-alkyl wherein C₁₋₆-alkyl is as definedabove. Representative examples are methylthio, ethylthio, isopropylthio,n-propylthio, butylthio, pentylthio and the like.

The term “C₁₋₆-alkylsulfonyl” as used herein, alone or in combination,refers to the radical —S(═O)₂—C₁₋₆-alkyl wherein C₁₋₆-alkyl is asdefined above. Representative examples are methylsulfonyl, ethysulfonyl,isopropylsulfonyl, n-propylsulfonyl, butylsulfonyl, pentylsulfonyl andthe like.

The term “C₁₋₇-alkanoyl” as used herein, alone or in combination, refersto the radical —C(═O)H or —C(═O)C₁₋₆-alkyl wherein C₁₋₆-alkyl is asdefined above. Representative examples are formyl, acetyl, propionyl,butanoyl, pentanoyl, hexanoyl, heptanoyl and the like.

The term “C₃₋₈-cycloalkyl” as used herein represents a monocyclic,carbocyclic group having from 3 to 8 carbon atoms. Representativeexamples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like.

The term “C₅₋₈-cycloalkenyl” as used herein represents a monocyclic,carbocyclic, non-aromatic group having from 5 to 8 carbon atoms and atleast one double bond. Representative examples are cyclopentenyl,cyclohexenyl, cyclohepentyl, cyclooctenyl, and the like.

The term “aryl” as used herein is intended to include carbocyclicaromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl,phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like.Aryl is also intended to include the partially hydrogenated derivativesof the carbocyclic systems enumerated above. Non-limiting examples ofsuch partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl,1,4-dihydronaphthyl and the like.

The term “aryloxy” as used herein refers to the radical —O-aryl wherearyl is as defined above. Non-limiting examples are phenoxy, naphthoxy,anthracenyloxy, phenantrenyloxy, fluorenyloxy, indenyloxy and the like.

The term “heteroaryl” as used herein is intended to include heterocyclicaromatic ring systems containing one or more heteroatoms selected fromnitrogen, oxygen and sulfur such as furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl,benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl,benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl,quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl,pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like.Heteroaryl is also intended to include the partially hydrogenatedderivatives of the heterocyclic systems enumerated above. Non-limitingexamples of such partially hydrogenated derivatives are2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl,oxazolidinyl, oxazolinyl, oxazepinyl and the like.

As used herein, the phrase “4 to 7 membered, saturated or unsaturatedheterocyclic ring” is intended to include heterocyclic rings which aresaturated or contain one or two double bonds.

Certain of the above defined terms may occur more than once in thestructural formulae, and upon such occurrence each term shall be definedindependently of the other.

The term “optionally substituted” as used herein means that the group inquestion is either unsubstituted or substituted with one or more of thesubstituents specified. When the group in question is substituted withmore than one substituent the substituents may be the same or different.

“Aryl-C₁₋₆-alkyl”, “aryl-C₁₋₆-alkoxy” etc. mean C₁₋₆-alkyl orC₁₋₆-alkoxy as defined above, substituted by aryl as defined above, forexample:

SUMMARY OF THE INVENTION

The invention relates to a compound of the general formula (I):

wherein

-   m is 0, 1 or 2,-   R¹ is-   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    -   which may optionally be substituted with one or more        substituents selected from halogen, C₁₋₆-alkoxy and hydroxy,-   C₃₋₈-cycloalkyl, C₅₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,    di(C₃₋₈-cycloalkyl)-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₂₋₆-alkenyl,    C₃₋₈-cycloalkyl-C₂₋₆-alkynyl, C₅₋₈-cycloalkenyl-C₁₋₆-alkyl,    C₅₋₈-cycloalkenyl-C₂₋₆-alkenyl, C₅₋₈-cycloalkenyl-C₂₋₆-alkynyl,    -   wherein the cyclic moieties may optionally be substituted with        one or more substituents selected from C₁₋₆-alkyl, halogen,        trifluoromethyl and 2,2,2-trifluoroethyl,-   R² is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or    C₃₋₈-cycloalkyl-C₁₋₆-alkyl,-   X is —CH₂—(CH₂)_(n)—, —(CH₂)_(n)—CH═CH—(CH₂)_(p)—,    —CH₂—(CH₂)_(n)—O—(CH₂)_(p)—, —CH₂—(CH₂)_(n)—C(═O)—(CH₂)_(p)—,    —CH₂—(CH₂)_(n)—S—(CH₂)_(p)—, —CH₂—(CH₂)_(n)—S(═O)—(CH₂)_(p)— or    —CH₂—(CH₂)_(n)—S(═O)₂—(CH₂)_(p)—,-   n and p are independently 0, 1, 2, 3 or 4,-   R³ and R⁴ are independently hydrogen, methyl or trifluoromethyl,-   Y is    -   (a) aryl or heteroaryl, which may optionally be substituted with        one or more substituents selected from        -   halogen, nitro, cyano, hydroxy, oxo, C₁₋₇-alkanoyl,            C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,            C₃₋₈-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR⁵R⁶            and —O(C═O)NR⁵R⁶,        -    wherein R⁵ and R⁶ independently are hydrogen, C₁₋₆-alkyl,            C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or R⁵ and R⁶            together with the nitrogen atom to which they are attached            form a 4 to 7 membered, saturated or unsaturated ring,        -   or wherein two substituents in adjacent positions form a            radical —O—(CH₂)₁₋₃—O—,        -   aryl, aryloxy, aryl-C₁₋₆-alkyl and aryl-C₁₋₆-alkoxy, wherein            the ring moieties optionally may be substituted with one or            more substituents selected from            -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,                C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkyl,                C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, trifluoromethyl,                trifluoromethoxy, —NR⁷R⁸ and —O(C═O)NR⁷R⁸,            -    wherein R⁷ and R⁸ independently are hydrogen,                C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or                R⁷ and R⁸ together with the nitrogen atom to which they                are attached form a 4 to 7 membered, saturated or                unsaturated ring,            -   or wherein two substituents in adjacent positions form a                radical —O—(CH₂)₁₋₃—O—    -   (b) C₃₋₈-cycloalkyl or C₅₋₈-cycloalkenyl, which may optionally        be substituted with one or more substituents selected from        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, cyano,            trifluoromethyl, trifluoromethoxy and halogen,        -   aryl and aryloxy, wherein the ring moieties optionally may            be substituted with one or more substituents selected from            -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,                C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy,                C₃₋₈-cycloalkyl, trifluoromethyl, trifluoromethoxy,                —NR⁹R¹⁰ and —O(C═O)NR⁹R¹⁰,            -    wherein R⁹ and R¹⁰ independently are hydrogen,                C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or                R⁹ and R¹⁰ together with the nitrogen atom to which they                are attached form a 4 to 7 membered, saturated or                unsaturated ring,    -   (c) C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl, which may        optionally be substituted with one or more substituents selected        from        -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,            C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy,            C₃₋₈-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR¹¹R¹²            and —O(C═O)NR¹¹R¹²,        -    wherein R¹¹ and R¹² independently are hydrogen, C₁₋₆-alkyl,            C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or R¹¹ and R¹²            together with the nitrogen atom to which they are attached            form a 4 to 7 membered, saturated or unsaturated ring,        -   aryl, aryl-C₁₋₆-alkyl and aryl-C₁₋₆-alkoxy, wherein the ring            moieties optionally may be substituted with one or more            substituents selected from            -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,                C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkyl,                C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, trifluoromethyl,                trifluoromethoxy, —NR¹³R¹⁴ and —O(C═O)NR¹³R¹⁴,            -    wherein R¹³ and R¹⁴ independently are hydrogen,                C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or                R¹³ and R¹⁴ together with the nitrogen atom to which                they are attached form a 4 to 7 membered, saturated or                unsaturated ring,            -   or wherein two substituents in adjacent positions form a                radical —O—(CH₂)₁₋₃—O—                with the proviso that the compound must not be

as well as any diastereomer or enantiomer or tautomeric form thereofincluding mixtures of these or a pharmaceutically acceptable saltthereof.

In one embodiment of the invention Y is

-   (a) aryl or heteroaryl, which may optionally be substituted with one    or more substituents selected from    -   halogen, nitro, cyano, hydroxy, oxo, C₁₋₇-alkanoyl,        C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₃₋₈-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR⁵R⁶ and        —O(C═O)NR⁵R⁶,    -    wherein R⁵ and R⁶ independently are hydrogen, C₁₋₆-alkyl,        C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or R⁵ and R⁶ together        with the nitrogen atom to which they are attached form a 4 to 7        membered, saturated or unsaturated ring,    -   or wherein two substituents in adjacent positions form a radical        —O—(CH₂)₁₋₃—O—,    -   aryl, aryl-C₁₋₆-alkyl and aryl-C₁₋₆-alkoxy, wherein the ring        moieties optionally may be substituted with one or more        substituents selected from        -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,            C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,            C₃₋₈-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR⁷R⁸            and —O(C═O)NR⁷R⁸,        -    wherein R⁷ and R⁸ independently are hydrogen, C₁₋₆-alkyl,            C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or R⁷ and R⁸            together with the nitrogen atom to which they are attached            form a 4 to 7 membered, saturated or unsaturated ring,        -   or wherein two substituents in adjacent positions form a            radical —O—(CH₂)₁₋₃—O—-   (b) C₃₋₈-cycloalkyl or C₅₋₈-cycloalkenyl, which may optionally be    substituted with one or more substituents selected from    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, cyano, trifluoromethyl,        trifluoromethoxy and halogen,    -   aryl and aryloxy, wherein the ring moieties optionally may be        substituted with one or more substituents selected from        -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,            C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy,            C₃₋₈-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR⁹R¹⁰            and —O(C═O)NR⁹R¹⁰,        -    wherein R⁹ and R¹⁰ independently are hydrogen, C₁₋₆-alkyl,            C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or R⁹ and R¹⁰            together with the nitrogen atom to which they are attached            form a 4 to 7 membered, saturated or unsaturated ring,-   (c) C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl, which may optionally    be substituted with one or more substituents selected from    -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl, C₁₋₆-alkylthio,        C₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy, C₃₋₈-cycloalkyl,        trifluoromethyl, trifluoromethoxy, —NR¹¹R¹² and —O(C═O)NR¹¹R¹²,    -    wherein R¹¹ and R¹² independently are hydrogen, C₁₋₆-alkyl,        C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or R¹¹ and R¹² together        with the nitrogen atom to which they are attached form a 4 to 7        membered, saturated or unsaturated ring,    -   aryl, aryl-C₁₋₆-alkyl and aryl-C₁₋₆-alkoxy, wherein the ring        moieties optionally may be substituted with one or more        substituents selected from        -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,            C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,            C₃₋₈-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR¹³R¹⁴            and —O(C═O)NR¹³R¹⁴,        -    wherein R¹³ and R¹⁴ independently are hydrogen, C₁₋₆-alkyl,            C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or R¹³ and R¹⁴            together with the nitrogen atom to which they are attached            form a 4 to 7 membered, saturated or unsaturated ring,        -   or wherein two substituents in adjacent positions form a            radical —O—(CH₂)₁₋₃—O—

In another embodiment of the invention m is 1.

In another embodiment of the invention R³ and R⁴ are both hydrogen.

In yet another embodiment of the invention R¹ is C₁₋₆-alkyl which mayoptionally be substituted with one or more substituents selected fromhalogen, C₁₋₆-alkoxy and hydroxy.

In an embodiment thereof R¹ is C₁₋₆-alkyl such as isopropyl, tert-butylor 2-methyl-2-butyl.

In still another embodiment of the invention R¹ isdi(C₃₋₈-cycloalkyl)-C₁₋₆-alkyl, wherein the cyclic moieties mayoptionally be substituted with one or more substituents selected fromC₁₋₆-alkyl, halogen, trifluoromethyl and 2,2,2-trifluoroethyl.

In an embodiment thereof R¹ is dicyclopropylmethyl.

In a further embodiment of the invention R² is C₁₋₆-alkyl.

In still a further embodiment of the invention X is —CH₂—(CH₂)_(n)—,—(CH₂)_(n)—CH═CH—(CH₂)_(p)—, —CH₂—(CH₂)_(n)—O—(CH₂)_(p)—,—CH₂—(CH₂)_(n)—C(═O)—(CH₂)_(p)—, —CH₂—(CH₂)_(n)—S—(CH₂)_(p)—, wherein nand p are as defined for formula (I).

In an embodiment thereof X is —CH₂—(CH₂)_(n)—, —CH═CH—,—CH₂—(CH₂)_(n)—O—, —CH₂—(CH₂)_(n)—C(═O)—, —CH₂—S—(CH₂)_(p)—, wherein nis 0, 1, 2 or 3, and p is 0 or 1.

In yet an embodiment thereof X is —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—CH═CH—, —CH₂—O—, —(CH₂)₃—O—, —(CH₂)₂—C(═O)—, —CH₂—S—CH₂— or —CH₂—S—,such as —CH₂—.

In another embodiment of the invention Y is C₁₋₆-alkyl, C₃₋₈-cycloalkyl,aryl or heteroaryl, which may optionally be substituted as defined forformula (I).

In an embodiment thereof Y is C₁₋₆-alkyl, cyclohexyl, phenyl, naphthyl,pyridyl, benzoxazolyl or benzothiophenyl, which may optionally besubstituted as defined for formula (I).

In yet an embodiment thereof Y is phenyl or naphthyl which mayoptionally be substituted with one or more substituents selected from

-   -   trifluoromethyl, trifluoromethoxy, halogen, C₁₋₆-alkyl, —NR⁵R⁶        and —O(C═O)NR⁵R⁶, C₁₋₇-alkanoyl, wherein R⁵ and R⁶ independently        are hydrogen, C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or        aryl, or R⁵ and R⁶ together with the nitrogen atom to which they        are attached form a 4 to 7 membered, saturated or unsaturated        ring,    -   aryl-C₁₋₆-alkoxy, aryl-C₁₋₆-alkyl, aryloxy, and aryl, which may        optionally be substituted with halogen or C₁₋₆-alkyl,    -   or wherein two substituents in adjacent positions form a radical        —O—(C₂)₁₋₃—O—.

In an embodiment thereof Y is phenyl or naphthyl which may optionally besubstituted with one or more substituents selected from

-   -   trifluoromethyl, trifluoromethoxy, halogen, C₁₋₆-alkyl, —NR⁵R⁶        and —O(C═O)NR⁵R⁶ and C₁₋₇-alkanoyl, wherein R⁵ and R⁶        independently are hydrogen or C₁₋₆-alkyl,    -   phenyl-C₁₋₆-alkoxy, phenyl-C₁₋₆-alkyl, phenyloxy and phenyl,        which may optionally be substituted with halogen or C₁₋₆-alkyl,    -   or wherein two substituents in adjacent positions form a radical        —O—(CH₂)₁₋₃—O—.

In yet an embodiment thereof Y is phenyl, which is substituted withphenyl.

The compounds of the present invention may be chiral, and it is intendedthat any enantiomers, as separated, pure or partially purifiedenantiomers or racemic mixtures thereof are included within the scope ofthe invention.

Furthermore, when a double bond or a fully or partially saturated ringsystem or more than one center of asymmetry or a bond with restrictedrotatability is presented in the molecule diastereomers may be formed.It is intended that any diastereomers, as separated, pure or partiallypurified diastereomers or mixtures thereof are included within the scopeof the invention.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric forms,which the compounds are able to form, are included within the scope ofthe present invention.

The present invention also encompasses pharmaceutically acceptable saltsof the present compounds. Such salts include pharmaceutically acceptableacid addition salts, pharmaceutically acceptable metal salts, ammoniumand alkylated ammonium salts. Acid addition salts include salts ofinorganic acids as well as organic acids. Representative examples ofsuitable inorganic acids include hydrochloric, hydrobromic, hydroiodic,phosphoric, sulfuric, nitric acids and the like. Representative examplesof suitable organic acids include formic, acetic, trichloroacetic,trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric,glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric,pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric,ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic,citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic,glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Furtherexamples of pharmaceutically acceptable inorganic or organic acidaddition salts include the pharmaceutically acceptable salts listed inJ. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.Examples of metal salts include lithium, sodium, potassium, magnesiumsalts and the like. Examples of ammonium and alkylated ammonium saltsinclude ammonium, methylammonium, dimethylammonium, trimethylammonium,ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium,tetramethylammonium salts and the like.

Also intended as pharmaceutically acceptable acid addition salts are thehydrates, which the present compounds are able to form.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent.

The compounds of the present invention may form solvates with standardlow molecular weight solvents using methods well known to the personskilled in the art. Such solvates are also contemplated as being withinthe scope of the present invention.

The invention also encompasses prodrugs of the present compounds, whichon administration undergo chemical conversion by metabolic processesbefore becoming active pharmacological substances. In general, suchprodrugs will be functional derivatives of the present compounds, whichare readily convertible in vivo into the required compound of theformula (I). Conventional procedures for the selection and preparationof suitable prodrug derivatives are described, for example, in “Designof Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The invention also encompasses active metabolites of the presentcompounds.

The compounds of the present invention interact with the histamine H3receptor and are accordingly useful for the treatment and/or preventionof a wide variety of conditions and disorders in which histamine H3receptor interactions are beneficial.

Accordingly, in another aspect the present invention relates to acompound of the general formula (I) as well as any diastereomer orenantiomer or tautomeric form thereof including mixtures of these or apharmaceutically acceptable salt thereof for use as a pharmaceuticalcomposition.

The invention also relates to pharmaceutical compositions comprising, asan active ingredient, at least one compound of the formula (I) or anydiastereomer or enantiomer or tautomeric form thereof including mixturesof these or a pharmaceutically acceptable salt thereof together with oneor more pharmaceutically acceptable carriers or diluents.

Furthermore, the invention relates to the use of a compound of thegeneral formula (I′):

wherein

-   m is 0, 1 or 2,-   R¹ is-   C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    -   which may optionally be substituted with one or more        substituents selected from halogen, C₁₋₆-alkoxy and hydroxy,-   C₃₋₈-cycloalkyl, C₅₋₈-cycloalkenyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,    di(C₃₋₈-cycloalkyl)-C₁₋₆-alkyl, C₃₋₈-cycloalkyl-C₂₋₆-alkenyl,    C₃₋₈-cycloalkyl-C₂₋₆-alkynyl, C₅₋₈-cycloalkenyl-C₁₋₆-alkyl,    C₅₋₈-cycloalkenyl-C₂₋₆-alkenyl, C₅₋₈-cycloalkenyl-C₂₋₆-alkynyl,    -   wherein the cyclic moieties may optionally be substituted with        one or more substituents selected from C₁₋₆-alkyl, halogen,        trifluoromethyl and 2,2,2-trifluoroethyl,-   R² is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or    C₃₋₈-cycloalkyl-C₁₋₆-alkyl,-   X is —CH₂—(CH₂)_(n)—, —(CH₂)_(n)—CH═CH—(CH₂)_(p)—,    —CH₂—(CH₂)_(n)—O—(CH₂)_(p)—, —CH₂—(CH₂)_(n)—C(═O)—(CH₂)_(p)—,    —CH₂—(CH₂)_(n)—S—(CH₂)_(p)—, —CH₂—(CH₂)_(n)—S(═O)—(CH₂)_(p)— or    —CH₂—(CH₂)_(n)—S(═O)₂—(CH₂)_(p)—,-   n and p are independently 0, 1, 2, 3 or 4,-   R³ and R⁴ are independently hydrogen, methyl or trifluoromethyl,-   Y is    -   (a) aryl or heteroaryl, which may optionally be substituted with        one or more substituents selected from        -   halogen, nitro, cyano, hydroxy, oxo, C₁₋₇-alkanoyl,            C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkyl, C₁₋₆-alkoxy,            C₃₋₈-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR⁵R⁶            and —O(C═O)NR⁵R⁶,        -    wherein R⁵ and R⁶ independently are hydrogen, C₁₋₆-alkyl,            C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or R⁵ and R⁶            together with the nitrogen atom to which they are attached            form a 4 to 7 membered, saturated or unsaturated ring,        -   or wherein two substituents in adjacent positions form a            radical —O—(CH₂)₁₋₃—O—,        -   aryl, aryloxy, aryl-C₁₋₆-alkyl and aryl-C₁₋₆-alkoxy, wherein            the ring moieties optionally may be substituted with one or            more substituents selected from            -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,                C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkyl,                C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, trifluoromethyl,                trifluoromethoxy, —NR⁷R⁸ and —O(C═O)NR⁷R⁸,            -    wherein R⁷ and R⁸ independently are hydrogen,                C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or                R⁷ and R⁸ together with the nitrogen atom to which they                are attached form a 4 to 7 membered, saturated or                unsaturated ring,            -   or wherein two substituents in adjacent positions form a                radical —O—(CH₂)₁₋₃—O—    -   (b) C₃₋₈-cycloalkyl or C₅₋₈-cycloalkenyl, which may optionally        be substituted with one or more substituents selected from        -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, cyano,            trifluoromethyl, trifluoromethoxy and halogen,        -   aryl and aryloxy, wherein the ring moieties optionally may            be substituted with one or more substituents selected from            -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,                C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy,                C₃₋₈-cycloalkyl, trifluoromethyl, trifluoromethoxy,                —NR⁹R¹⁰ and —O(C═O)NR⁹R¹⁰,            -    wherein R⁹ and R¹⁰ independently are hydrogen,                C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or                R⁹ and R¹⁰ together with the nitrogen atom to which they                are attached form a 4 to 7 membered, saturated or                unsaturated ring,    -   (c) C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl, which may        optionally be substituted with one or more substituents selected        from        -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,            C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkoxy,            C₃₋₈-cycloalkyl, trifluoromethyl, trifluoromethoxy, —NR¹¹R¹²            and —O(C═O)NR¹¹R¹²,        -    wherein R¹¹ and R¹² independently are hydrogen, C₁₋₆-alkyl,            C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or R¹¹ and R¹²            together with the nitrogen atom to which they are attached            form a 4 to 7 membered, saturated or unsaturated ring,        -   aryl, aryl-C₁₋₆-alkyl and aryl-C₁₋₆-alkoxy, wherein the ring            moieties optionally may be substituted with one or more            substituents selected from            -   halogen, nitro, cyano, hydroxy, C₁₋₇-alkanoyl,                C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl, C₁₋₆-alkyl,                C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, trifluoromethyl,                trifluoromethoxy, —NR¹³R¹⁴ and —O(C═O)NR¹³R¹⁴,            -    wherein R¹³ and R¹⁴ independently are hydrogen,                C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₇-alkanoyl or aryl, or                R¹³ and R¹⁴ together with the nitrogen atom to which                they are attached form a 4 to 7 membered, saturated or                unsaturated ring,            -   or wherein two substituents in adjacent positions form a                radical —O—(CH₂)₁₋₃—O—                as well as any diastereomer or enantiomer or tautomeric                form thereof including mixtures of these or a                pharmaceutically acceptable salt thereof for the                preparation of a pharmaceutical composition for the                treatment and/or prevention of disorders and diseases                related to the histamine H3 receptor.

In still another aspect, the invention relates to a method for thetreatment and/or prevention of diseases and disorders related to thehistamine H3 receptor the method comprising administering to a subjectin need thereof an effective amount of a compound of the formula (I′) orany diastereomer or enantiomer or tautomeric form thereof includingmixtures of these or a pharmaceutically acceptable salt thereof or apharmaceutical composition comprising the same.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the invention relates to compounds with histamine H3receptor antagonistic activity or inverse agonistic activity which mayaccordingly be useful in the treatment of a wide range of conditions anddisorders in which histamine H3 receptor blockade is beneficial.

In another aspect the invention relates to compounds with histamine H3receptor agonistic activity and which may accordingly be useful in thetreatment of a wide range of conditions and disorders in which histamineH3 receptor activation is beneficial.

In a preferred embodiment of the invention the present compounds areused for the preparation of a pharmaceutical composition for thereduction of weight.

In a preferred embodiment of the invention the present compounds areused for the preparation of a pharmaceutical composition for thetreatment and/or prevention of overweight or obesity.

In another preferred embodiment of the invention the present compoundsare used for the preparation of a pharmaceutical composition for thesuppression of appetite or satiety induction.

In a further preferred embodiment of the invention the present compoundsare used for the preparation of a pharmaceutical composition for theprevention and/or treatment of disorders and diseases related tooverweight or obesity such as atherosclerosis, hypertension, IGT(impaired glucose tolerance), diabetes, especially Type 2 diabetes(NIDDM (non-insulin dependent diabetes mellitus)), dyslipidaemia,coronary heart disease, gallbladder disease, osteoarthritis and varioustypes of cancer such as endometrial, breast, prostate and colon cancers.

In yet a further preferred embodiment of the invention the presentcompounds are used for the preparation of a pharmaceutical compositionfor the prevention and/or treatment of eating disorders such as bulimiaand binge eating.

In a further preferred embodiment of the invention the present compoundsare used for the preparation of a pharmaceutical composition for thetreatment and/or prevention of IGT.

In a further preferred embodiment of the invention the present compoundsare used for the preparation of a pharmaceutical composition for thetreatment and/or prevention of Type 2 diabetes.

In another preferred embodiment of the invention the present compoundsare used for the preparation of a pharmaceutical composition for thedelaying or prevention of the progression from IGT to Type 2 diabetes.

In a further preferred embodiment of the invention the present compoundsare used for the preparation of a pharmaceutical composition for thedelaying or prevention of the progression from non-insulin requiringType 2 diabetes to insulin requiring Type 2 diabetes.

The compounds of the present invention may also be used for thetreatment of airway disorders such as asthma, as anti-diarrhoeals andfor the modulation of gastric acid secretion.

Furthermore, the compounds of the present invention may be used for thetreatment of diseases associated with the regulation of sleep andwakefulness and for the treatment of narcolepsy and attention deficitdisorders.

Moreover, the compounds of the invention may be used as CNS stimulantsor as sedatives.

The present compounds may also be used for the treatment of conditionsassociated with epilepsy. Additionally, the present compounds may beused for the treatment of motion sickness and vertigo. Furthermore, theymay be useful as regulators of hypothalamohypophyseal secretion,antidepressants, modulators of cerebral circulation, and in thetreatment of irritable bowel syndrome.

Further, the compounds of the present invention may be used for thetreatment of dementia and Alzheimer's disease.

The compounds of the present invention may also be useful for thetreatment of allergic rhinitis, ulcer or anorexia.

The compounds of the present invention may furthermore be useful for thetreatment of migraine, see. R. L. McLeod et al., The Journal ofPharmacology and Experimental Therapeutics 287 (1998), 43-50, and forthe treatment of myocardial infarction, see C. J. Mackins and R. Levi,Expert Opinion on Investigational Drugs 9 (2000), 2537-2542.

In a further aspect of the invention the present compounds are combinedwith diet and/or exercise.

In a further aspect of the invention the present compounds may beadministered in combination with one or more further pharmacologicallyactive substances in any suitable ratios. Such further active agents maybe selected from antiobesity agents, antidiabetics, antihypertensiveagents, agents for the treatment and/or prevention of complicationsresulting from or associated with diabetes and agents for the treatmentand/or prevention of complications and disorders resulting from orassociated with obesity.

Thus, in a further aspect of the invention the present compounds may beadministered in combination with one or more antiobesity agents orappetite regulating agents.

Such agents may be selected from the group consisting of CART (cocaineamphetamine regulated transcript) agonists, NPY (neuropeptide Y)antagonists, MC4 (melanocortin 4) agonists, MC3 (melanocortin 3)agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF(corticotropin releasing factor) agonists, CRF BP (corticotropinreleasing factor binding protein) antagonists, urocortin agonists, β3adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884,LY377267 or AZ-40140, MSH (melanocyte-stimulating hormone) agonists, MCH(melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin)agonists, serotonin re-uptake inhibitors such as fluoxetine, seroxat orcitalopram, serotonin and noradrenaline re-uptake inhibitors, mixedserotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth factorssuch as prolactin or placental lactogen, growth hormone releasingcompounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3(uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists(bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisomeproliferator-activated receptor) modulators, RXR (retinoid X receptor)modulators, TR β agonists, AGRP (Agouti related protein) inhibitors,opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliaryneurotrophic factor.

In one embodiment of the invention the antiobesity agent is leptin.

In another embodiment the antiobesity agent is dexamphetamine oramphetamine.

In another embodiment the antiobesity agent is fenfluramine ordexfenfluramine.

In still another embodiment the antiobesity agent is sibutramine.

In a further embodiment the antiobesity agent is orlistat.

In another embodiment the antiobesity agent is mazindol or phentermine.

In still another embodiment the antiobesity agent is phendimetrazine,diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.

Suitable antidiabetic agents comprise insulin, insulin analogues andderivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), egN^(εB29)-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705275 (Novo Nordisk A/S), eg Asp^(B28) human insulin, U.S. Pat. No.5,504,188 (Eli Lilly), eg Lys^(B28) Pro^(B29) human insulin, EP 368 187(Aventis), eg Lantus, which are all incorporated herein by reference,GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo NordiskA/S), which is incorporated herein by reference, as well as orallyactive hypoglycaemic agents.

The orally active hypoglycaemic agents preferably comprise imidazolines,sulphonylureas, biguanides, meglitinides, oxadiazolidinediones,thiazolidinediones, insulin sensitizers, α-glucosidase inhibitors,agents acting on the ATP-dependent potassium channel of the β-cells egpotassium channel openers such as those disclosed in WO 97/26265, WO99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporatedherein by reference, or mitiglinide, or a potassium channel blocker,such as BTS-67582, nateglinide, glucagon antagonists such as thosedisclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and AgouronPharmaceuticals, Inc.), which are incorporated herein by reference,GLP-1 agonists such as those disclosed in WO 00/42026 (Novo Nordisk A/Sand Agouron Pharmaceuticals, Inc.), which are incorporated herein byreference, DPP-IV (dipeptidyl peptidase-IV) inhibitors, PTPase (proteintyrosine phosphatase) inhibitors, inhibitors of hepatic enzymes involvedin stimulation of gluconeogenesis and/or glycogenolysis, glucose uptakemodulators, GSK-3 (glycogen synthase kinase-3) inhibitors, compoundsmodifying the lipid metabolism such as antilipidemic agents, compoundslowering food intake, PPAR (peroxisome proliferator-activated receptor)and RXR (retinoid X receptor) agonists, such as ALRT-268, LG-1268 orLG-1069.

In one embodiment of the invention the present compounds areadministered in combination with insulin.

In a further embodiment of the invention the present compounds areadministered in combination with a sulphonylurea eg tolbutamide,chlorpropamide, tolazamide, glibenclamide, glipizide, glimepiride,glicazide or glyburide.

In another embodiment of the invention the present compounds areadministered in combination with a biguanide eg metformin.

In yet another embodiment of the invention the present compounds areadministered in combination with a meglitinide eg repaglinide ornateglinide.

In still another embodiment of the invention the present compounds areadministered in combination with a thiazolidinedione insulin sensitizereg troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone,darglitazone, englitazone, CS-011/CI-1037 or T 174 or the compoundsdisclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO98/45292 (Dr. Reddy's Research Foundation), which are incorporatedherein by reference.

In still another embodiment of the invention the present compounds maybe administered in combination with an insulin sensitizer eg such as GI262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544,CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or thecompounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO00/63192, WO 00/63193 (Dr. Reddy's Research Foundation) and WO 00/23425,WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189 (NovoNordisk A/S), which are incorporated herein by reference.

In a further embodiment of the invention the present compounds areadministered in combination with an α-glucosidase inhibitor egvoglibose, emiglitate, miglitol or acarbose.

In another embodiment of the invention the present compounds areadministered in combination with an agent acting on the ATP-dependentpotassium channel of the β-cells eg tolbutamide, glibenclamide,glipizide, glicazide, BTS-67582 or repaglinide.

In yet another embodiment of the invention the present compounds may beadministered in combination with nateglinide.

In still another embodiment of the invention the present compounds areadministered in combination with an antilipidemic agent egcholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin,pravastatin, simvastatin, probucol or dextrothyroxine.

In another aspect of the invention, the present compounds areadministered in combination with more than one of the above-mentionedcompounds eg in combination with metformin and a sulphonylurea such asglyburide; a sulphonylurea and acarbose; nateglinide and metformin;acarbose and metformin; a sulfonylurea, metformin and troglitazone;insulin and a sulfonylurea; insulin and metformin; insulin, metforminand a sulfonylurea; insulin and troglitazone; insulin and lovastatin;etc.

Furthermore, the present compounds may be administered in combinationwith one or more antihypertensive agents. Examples of antihypertensiveagents are β-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, quinapril and ramipril, calcium channel blockers such asnifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazemand verapamil, and α-blockers such as doxazosin, urapidil, prazosin andterazosin. Further reference can be made to Remington: The Science andPractice of Pharmacy, 19^(th) Edition, Gennaro, Ed., Mack PublishingCo., Easton, Pa., 1995.

It should be understood that any suitable combination of the compoundsaccording to the invention with diet and/or exercise, one or more of theabove-mentioned compounds and optionally one or more other activesubstances are considered to be within the scope of the presentinvention.

PHARMACEUTICAL COMPOSITIONS

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)route, the oral route being preferred. It will be appreciated that thepreferred route will depend on the general condition and age of thesubject to be treated, the nature of the condition to be treated and theactive ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosageforms such as capsules, tablets, dragees, pills, lozenges, powders andgranules. Where appropriate, they can be prepared with coatings such asenteric coatings or they can be formulated so as to provide controlledrelease of the active ingredient such as sustained or prolonged releaseaccording to methods well known in the art.

Liquid dosage forms for oral administration include solutions,emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and non-aqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Depotinjectable formulations are also contemplated as being within the scopeof the present invention.

Other suitable administration forms include suppositories, sprays,ointments, cremes, gels, inhalants, dermal patches, implants etc.

A typical oral dosage is in the range of from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kgbody weight per day, and more preferred from about 0.05 to about 10mg/kg body weight per day administered in one or more dosages such as 1to 3 dosages. The exact dosage will depend upon the frequency and modeof administration, the sex, age, weight and general condition of thesubject treated, the nature and severity of the condition treated andany concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may conveniently be presented in unit dosage form bymethods known to those skilled in the art. A typical unit dosage formfor oral administration one or more times per day such as 1 to 3 timesper day may contain of from 0.05 to about 1000 mg, preferably from about0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200mg.

For parenteral routes, such as intravenous, intrathecal, intramuscularand similar administration, typically doses are in the order of abouthalf the dose employed for oral administration.

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. One exampleis an acid addition salt of a compound having the utility of a freebase. When a compound of the formula (I) contains a free base such saltsare prepared in a conventional manner by treating a solution orsuspension of a free base of the formula (I) with a chemical equivalentof a pharmaceutically acceptable acid, for example, inorganic andorganic acids. Representative examples are mentioned above.Physiologically acceptable salts of a compound with a hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as sodium or ammonium ion.

For parenteral administration, solutions of the novel compounds of theformula (I) in sterile aqueous solution, aqueous propylene glycol orsesame or peanut oil may be employed. Such aqueous solutions should besuitable buffered if necessary and the liquid diluent first renderedisotonic with sufficient saline or glucose. The aqueous solutions areparticularly suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

Suitable pharmaceutical carriers include inert solid diluents orfilters, sterile aqueous solution and various organic solvents. Examplesof solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc,gelatine, agar, pectin, acacia, magnesium stearate, stearic acid orlower alkyl ethers of cellulose. Examples of liquid carriers are syrup,peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines,polyoxyethylene or water. Similarly, the carrier or diluent may includeany sustained release material known in the art, such as glycerylmonostearate or glyceryl distearate, alone or mixed with a wax. Thepharmaceutical compositions formed by combining the novel compounds ofthe formula (I) and the pharmaceutically acceptable carriers are thenreadily administered in a variety of dosage forms suitable for thedisclosed routes of administration. The formulations may conveniently bepresented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, and whichmay include a suitable excipient. These formulations may be in the formof powder or granules, as a solution or suspension in an aqueous ornon-aqueous liquid, or as an oil-in-water or water-in-oil liquidemulsion.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatine capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatine capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

A typical tablet, which may be prepared by conventional tablettingtechniques, may contain:

Core:

-   -   Active compound (as free compound or salt thereof) 5.0 mg    -   Lactosum Ph. Eur. 67.8 mg    -   Cellulose, microcryst. (Avicel) 31.4 mg    -   Amberlite® IRP88* 1.0 mg    -   Magnesii stearas Ph. Eur. q.s. *Polacrillin potassium NF, tablet        disintegrant, Rohm and Haas.        Coating:    -   Hydroxypropyl methylcellulose approx. 9 mg    -   Mywacett 9-40 T** approx. 0.9 mg **Acylated monoglyceride used        as plasticizer for film coating.

If desired, the pharmaceutical composition of the invention may comprisethe compound of the formula (I) in combination with furtherpharmacologically active substances such as those described in theforegoing.

EXAMPLES

The preparation of the compounds of this invention can be realized inmany different ways. The compounds of the present invention wereprepared using standard synthetic procedures, well-known by thoseskilled in the art, as described, for instance, in Houben Weyl: Methodender Organischen Chemie, Thieme Verlag, Stuttgart.

The amides were prepared either in solution or with the aid of aninsoluble nitrophenol from the corresponding amines and carboxylicacids, using standard methodology (see eg J. J. Parlow, J. E.Normansell, Mol. Diversity 1996, 1, 266-269; R. Kalir, M. Fridkin, A.Patchornik, Eur. J. Biochem. 1974, 42, 151-156; B. J. Cohen, H.Karoly-Hafeli, A. Patchornik, J. Org. Chem. 1984, 49, 922-924). Insolution the carboxylic acid was activated by treatment with carbonyldiimidazole or di-(N-succinimidyl)carbonate and then treated with theamine. The carbamates were prepared by activating an alcohol withphosgene or 4-nitrophenyl chloroformate, and treating the resultingchloroformate or 4-nitrophenyl carbonate with an amine. The ureas wereprepared by treating an amine with a suitable isocyanate or carbamoylchloride.

In the examples the following terms are intended to have the following,general meanings:

-   DCM: dichloromethane, methylenechloride-   DIC: diisopropylcarbodiimide-   DMF: N,N-dimethyl formamide-   DMSO: dimethyl sulphoxide-   THF: tetrahydrofuran-   PS: Polystyrene

NMR spectra were recorded on Bruker 300 MHz and 400 MHz instruments.HPLC-MS was performed on a Perkin Elmer instrument (API 100).

HPLC-systems from Merck-Hitachi (Hibar™ TR 250-4, Lichrosorb™ RP 18, 5.0μm, 4.0×250 mm, gradient elution, 20% to 80% acetonitrile in waterwithin 30 min, 1.0 ml/min, detection at 254 nm) and Waters (Symmetry™,C18, 3.5 μm, 3.0×150 mm, gradient elution, 5% to 90% acetonitrile inwater within 15 min, 1.0 ml/min, detection at 214 nm) were used.

Furthermore, where stated the following HPLC method h8 was used:

The reverse phase analysis was performed using UV detections at 214,254, 276 and 301 nm on a 218TP54 4.6 mm×150 mm C-18 silica column, whichwas eluted at 1 ml/min at 42° C. The column was equilibrated with 5%acetonitrile, 85% water and 10% of a solution of 0.5% trifluoroaceticacid in water and eluted by a linear gradient from 5% acetonitrile, 85%water and 10% of a solution of 0.5% trifluoroacetic acid to 90%acetonitrile and 10% of a solution of 0.5% trifluoroacetic acid over 15min.

General Procedures for the Preparation of Compounds of the GeneralFormula (I):

An insoluble nitrophenol was prepared by acylating commerciallyavailable aminomethyl polystyrene (1% cross-linked with divinyl benzene,0.8 mmol/g) with 4-hydroxy-3-nitrobenzoic acid. The resulting supportwas acylated with a carboxylic acid (DCM/DMF, DIC, 2 hours, roomtemperature), filtered and washed with three times with DCM and thentreated with less than one equivalent of an amine (DCM/acetonitrile,room temperature, overnight). Filtration and concentration yielded thepure products, which were either tested directly, or further purified byrecrystallization or column chromatography. The products were analyzedby ¹H NMR and HPLC-MS.

Most of the 4-aminopiperidines required for the preparation of thecompounds of the present invention were commercially available. Thepreparation of those amines which were not commercially available isdescribed below.

1-Isopropyl-4-methylaminopiperidine

To a stirred mixture of methylamine hydrochloride (2.62 g, 38.8 mmol),THF (30 ml), ethanol (15 ml), N-isopropyl-4-piperidinone (3.0 ml, 20.2mmol), and acetic acid (3.60 ml) was added sodium cyanoborohydride (30ml, 1 molar solution in THF, 30 mmol), and the mixture was stirred at60° C. for 6 hours and then at room temperature overnight. The mixturewas concentrated under reduced pressure, water (50 ml) and potassiumcarbonate (47.0 g) were added, and the mixture was extracted with ethylacetate (6×50 ml). The combined extracts were dried over magnesiumsulphate and concentrated, to yield 3.78 g (quant.) of the titlecompound as an oil, which was used without further purification.

Typical Procedure:

Example 11

2-Biphenyl-4-yl-N-methyl-N-(1-methylpiperidin-4-yl)acetamideHydrochloride

To the polymeric nitrophenol (1.5 g, approx. 1 mmol) was added afiltered solution of 4-biphenylylacetic acid (1.10 g, 5.18 mmol) in amixture of 1,2-dichloropropane (18 ml) and DMF (2 ml), followed by theaddition of a solution of DIC (0.63 g, 4.99 mmol) in 1,2-dichloropropane(5 ml). The mixture was shaken at room temperature for 15 hours,filtered, and the polymer was extensively washed with DCM, DMF, and1,2-dichloropropane. To the polymer was added 1,2-dichloropropane (5 ml)and a solution of 1-methyl-4-methylaminopiperidine (0.10 g, 0.78 mmol)in 1,2-dichloropropane (10 ml). The resulting mixture was shaken at roomtemperature for 21 hours and then at 60° C. for one hour, filtered, andthe polymer was carefully washed with DCM and methanol. The combinedfiltrates were concentrated to yield the crude product, which waspurified by column chromatography (silicagel, gradient elution withDCM/methanol). The amine was mixed with ethanol and 1 molar aqueoushydrochloric acid, concentrated, and the residual hydrochloride wasrecrystallized from acetone. 120 mg (42%) of the title compound wasobtained.

¹H NMR (400 MHz, DMSO, mixture of rotamers): δ 1.64 (m, 2H), 2.05 (m,2H), 2.71 (m, 4H), 2.87 (s, 2H), 3.06 (m, 2H), 3.41 (m, 2H), 3.75 and3.83 (2×s, 2H), 4.13 (m, 0.5H), 4.54 (m, 0.5H), 7.27-7.38 (m, 3H), 7.45(t, J=8 Hz, 2H), 7.58-7.66 (m, 4H), 10.25 (m, 1H); HPLC-MS: m/z 323(MH⁺); R_(t): 4.1 min.

Using this methodology the following compounds were prepared:

Found Example Structure Name MH+ 1

3-[4-(4-Fluorobenzyloxy)phenyl]-N- methyl-N-(1-methylpiperidin-4-yl)-acrylamide 383 2

3-(4-Chlorophenyl)-N-methyl-N-(1- methylpiperidin-4-yl)propionamide 2953

2-Biphenyl-4-yl-N-cyclopropyl-N-(1- propylpiperidin-4-yl)acetamide 377 4

N-Methyl-N-(1-methylpiperidin-4-yl)-3-(4-trifluoromethylphenyl)propionamide 329 5

2-Biphenyl-4-yl-N-(1-isopropyl- piperidin-4-yl)-N-methylacetamide 351 6

2-(2-Methoxyphenoxy)-N-methyl-N- (1-methylpiperidin-4-yl)acetamide 293 7

3-(2-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)acrylamide 289 8

2-(2-Chlorophenoxy)-N-methyl-N-(1- methylpiperidin-4-yl)acetamide 297 9

N-Methyl-N-(1-methylpiperidin-4-yl)-3- naphthalen-1-ylacrylamide 309 10

3-(5-Bromo-2-ethoxyphenyl)-N- methyl-N-(1-methylpiperidin-4-yl)-acrylamide 381 11

2-Biphenyl-4-yl-N-methyl-N-(1- methylpiperidin-4-yl)acetamide 323 12

3-(3-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)acrylamide 28913

4-(4-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)butyramide 30514

2-(2,4-Dichloro-5-methylphenyl- sulfanyl)-N-methyl-N-(1-methyl-piperidin-4-yl)acetamide 362 15

4-(3-Fluoro-4-methoxyphenyl)-N- methyl-N-(1-methylpiperidin-4-yl)-4-oxobutyramide 337 16

3-(4-Dimethylaminophenyl)-N-methyl- N-(1-methytpiperidin-4-yl)acryiamide302 17

2-(2-Benzyloxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)acetamide 35318

3-(3,4-Dimethoxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)propionamide321 19

4-(2,4-Dichlorophenoxy)-N-methyl-N- (1-methylpiperidin-4-yl)butyramide360 20

3-(2-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)propionamide 39121

4-(4-Chloro-2-methylphenoxy)-N- methyl-N-(1-methylpiperidin-4-yl)-butyramide 339 22

2-(4-Fluorophenylsulfanyl)-N-methyl- N-(1-methylpiperidin-4-yl)acetamide297 23

3-(4-Fluoro-3-trifluoromethylphenyl)-N-methyl-N-(1-methylpiperidin-4-yl)- acrylamide 345 24

N-Methyl-N-(1-methylpiperidin-4-yl)-2-(3-trifluoromethoxyphenyl)acetamide 331 25

2-(4-Fluorophenoxy)-N-methyl-N-(1- methylpiperidin-4-yl)acetamide 281 26

2-(2,3-Dichlorophenoxy)-N-methyl-N- (1-methylpiperidin-4-yl)acetamide332 27

2-(4-Methoxyphenoxy)-N-methyl-N- (1-methytpiperidin-4-yl)acetamide 29328

N-Methyl-N-(1-methylpiperidin-4-yl)-2-(4-trifluoromethoxyphenyl)acetamide 331 29

3-Benzo[1,3]dioxol-5-yl-N-methyl-N- (1-methylpiperidin-4-yl)propionamide305 30

N-Methyl-N-(1-methylpiperidin-4-yl)-2- (naphthalen-2-yloxy)acetamide 31331

N-Methyl-N-(1-methylpiperidin-4-yl)-3-(3,4,5-trimethoxyphenyl)propionamide 351 32

3-(2,4-Dimethoxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)acrylamide319 33

4-Biphenyl-4-yl-N-methyl-N-(1- methylpiperidin-4-yl)-4-oxobutyramide 36534

N-Methyl-N-(1-methylpiperidin-4-yl)-2-(naphthalen-2-ylsulfanyl)acetamide 329 35

3-(3,5-Dimethoxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)acrylamide319 36

3-(2,3-Dimethoxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)acrylamide319 37

4-(3,4-Dimethoxyphenyl)-N-methyl-N- (1-methylpiperidin-4-yl)butyramide335 38

2-(2,3-Dimethyiphenoxy)-N-methyl-N- (1-methylpiperidin-4-yl)acetamide291 39

2-(8-Chloronaphthalen-1-ylsulfanyl)-N-methyl-N-(1-methylpiperidin-4-yl)- acetamide 363 40

N-Methyl-N-(1-methylpiperidin-4-yl)-2- (naphthalen-1-yloxy)acetamide 31341

2-(4-Acetylphenoxy)-N-methyl-N-(1- methylpiperidin-4-yl)acetamide 305 42

3-(3-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)propionamide 29143

N-Methyl-N-(1-methylpiperidin-4-yl)-3- pyridin-3-ylpropionamide 262 44

3-(4-Benzyloxy-3-methoxyphenyl)-N- methyl-N-(1-methylpiperidin-4-yl)-acrylamide 395 45

3-(5-Bromo-2-ethoxyphenyl)-N- methyl-N-(1-methylpiperidin-4-yl)-acrylamide 382 46

4-(3,4-Dihydro-2H-benzo[b][1,4]- dioxepin-7-yl)-N-methyl-N-(1-methyl-piperidin-4-yl)-4-oxobutyramide 361 47

3-(2-Chloro-3,4-dimethoxyphenyl)-N- methyl-N-(1-methylpiperidin-4-yl)-acrylamide 353 48

2-(2-Chloro-4-fluorophenylsulfanyl)-N-methyl-N-(1-methylpiperidin-4-yl)- acetamide 331 49

N-Methyl-N-(1-methylpiperidin-4-yl)-2- (naphthalen-1-ylmethylsulfanyl)-acetamide 343 50

N-Methyl-N-(1-methylpiperidin-4-yl)-3- (2-oxo-benzooxazol-3-yl)propion-amide 318 51

5-Cyclohexylpentanoic acid methyl- (1-methylpiperidin-4-yl)amide 295 52

3-(4-Methoxyphenyl)-N-methyl-N-(1- methylpiperidin-4-yl)propionamide 29153

N-Methyl-N-(1-methylpiperidin-4-yl)-2- (4-trifluoromethoxyphenoxy)acet-amide 247 54

2-(2-Acetylphenoxy)-N-methyl-N-(1- methylpiperidin-4-yl)acetamide 305 55

Dimethylcarbamic acid 4-{2-[methyl- (1-methylpiperidin-4-yl)carbamoyl]-ethyl}-phenyl ester 348 56

2-(5-Chloro-3-methyl-benzo[b]thio- phen-2-yl)-N-methyl-N-(1-methyl-piperidin-4-yl)acetamide 351

Spectral Data for Selected Examples

Example 2

3-(4-Chlorophenyl)-N-methyl-N-(1-methylpiperidin-4-yl)propionamidehydrochloride

¹H NMR (400 MHz, DMSO, mixture of rotamers): δ 1.55-1.76 (m, 2H), 2.05(m, 2H), 2.56-2.83 (m, 9H), 3.05 (m, 2H), 3.39 (m, 2H), 3.95 (m, 1H),4.52 (m, 1H), 7.30 (m, 4H), 10.36 (br s, 1H); HPLC-MS: m/z 295 (MH⁺);R_(t): 4.1 min.

Example 3

2-Biphenyl-4-yl-N-cyclopropyl-N-(1-propylpiperidin-4-yl)acetamidehydrochloride

¹H NMR (400 MHz, DMSO, mixture of rotamers): δ 0.89 (m, 7H), 1.68 (m,2H), 1.82 (m, 2H), 2.38 (m, 2H), 2.63 (m, 1H), 2.93 (m, 4H), 3.46 (m,2H), 3.91 (s, 2H), 4.03 (m, 1H), 7.29-7.38 (m, 3H), 7.46 (t, J=8 Hz,2H), 7.58-7.68 (m, 4H), 9.84 (br s, 1H); HPLC-MS: m/z 377 (MH⁺); R_(t):5.0 min.

Example 5

2-Biphenyl-4-yl-N-(1-isopropylpiperidin-4-yl)-N-methylacetamidehydrochloride

¹H NMR (400 MHz, DMSO, mixture of rotamers): δ 1.18-1.30 (m, 6H), 1.66(m, 2H), 2.10-2.32 (m, 3H), 2.82 and 2.89 (2×s, 3H), 3.08 (m, 3H), 3.76and 3.82 (2×s, 2H), 4.25 (m, 1H), 4.61 (m, 1H), 7.28-7.39 (m, 3H), 7.46(t, J=8 Hz, 2H), 7.58-7.68 (m, 4H), 10.1 (br.s, 1H); HPLC-MS: m/z 351(MH⁺); R_(t): 4.5 min.

PHARMACOLOGICAL METHODS

The ability of the compounds to interact with the histamine H3 receptorcan be determined by the following in vitro binding assays.

Binding Assay (I)

Rat cerebral cortex is homogenized in ice cold K-Hepes, 5 mM MgCl₂ pH7.1 buffer. After two differential centrifugations the last pellet isresuspended in fresh Hepes buffer containing 1 mg/ml bacitracin.Aliquots of the membrane suspension (400 μg/ml) are incubated for 60 minat 25° C. with 30 pM [¹²⁵I]-iodoproxifan, a known histamine H3 receptorantagonist, and the test compound at various concentrations. Theincubation is stopped by dilution with ice-cold medium, followed byrapid filtration through Whatman GF/B filters pretreated for 1 hour with0.5% polyethyleneimine. The radioactivity retained on the filters iscounted using a Cobra II auto gamma counter. The radioactivity of thefilters is indirectly proportional to the binding affinity of the testedcompound. The results are analyzed by nonlinear regression analysis.

Binding Assay (II)

The H3-receptor agonist ligand R-α-methyl[³H]histamine (RAMHA) isincubated with isolated rat cortex cell-membranes at 25° C. for 1 hour,followed by a filtration of the incubate through Whatman GF/B filters.Radioactivity retained on the filters is measured using a beta counter.

Male Wistar rats (150-200 g) are decapitated and cerebral cortex isquickly dissected out and frozen immediately on dry ice. Tissue is keptat −80° C. until membrane preparation. During the membrane preparationthe tissue is kept on ice all the time. Rat cerebral cortex ishomogenized in 10 volumes (w/w) ice-cold Hepes buffer (20 mM Hepes, 5 mMMgCl₂ pH 7.1 (KOH)+1 mg/ml bacitracin) using an Ultra-Turrax homogenizerfor 30 seconds. The homogenate is centrifuged at 140 g in 10 min. Thesupernatant is transferred to a new test tube and centrifuged for 30 minat 23 000 g. Pellet is resuspended in 5-10 ml Hepes buffer, homogenizedand centrifuged for 10 min at 23 000 g. This short centrifugation stepis repeated twice. After the last centrifugation the pellet isresuspended in 2-4 ml Hepes buffer and the protein concentration isdetermined. The membranes are diluted to a protein concentration of 5mg/ml using Hepes buffer, aliquoted and stored at −80° C. until use.

50 μl test-compound, 100 μl membrane (200 μg/ml), 300 μl Hepes bufferand 50 μl R-α-methyl[³H]histamine (1 nM) are mixed in a test tube. Thecompounds to be tested are dissolved in DMSO and further diluted in H₂Oto the desired concentrations. Radioligand and membranes are diluted inHepes buffer+1 mg/ml bacitracin. The mixture is incubated for 60 min at25° C. Incubation is terminated by adding 5 ml ice-cold 0.9% NaCl,followed by rapid filtration through Whatman GF/B filters pre-treatedfor 1 hour with 0.5% polyethyleneimine. The filters are washed with 2×5ml ice-cold NaCl. To each filter a 3 ml scintillation cocktail is addedand the radioactivity retained is measured with a Packard Tri-Carb betacounter.

IC₅₀ values are calculated by non-linear regression analysis of bindingcurves (6 points minimum) using the windows program GraphPad Prism,GraphPad software, USA.

Binding Assay (III)

The human H3 receptor is cloned by PCR and subcloned into the pcDNA3expression vector. Cells stably expressing the H3 receptor are generatedby transfecting the H3-expression vectors into HEK 293 cells and usingG418 to select for H3 clones. The human H3-HEK 293 clones are culturedin DMEM (GIBCO-BRL) with glutamax, 10% foetal calf serum, 1%penicillin/streptavidin and 1 mg/ml G 418 at 37° C. and 5% CO₂. Beforeharvesting, the confluent cells are rinsed with PBS and incubated withVersene (proteinase, GIBCO-BRL) for approximately 5 min. The cells areflushed with PBS and DMEM and the cellsuspension collected in a tube andcentrifuged for 5-10 min at 1500 rpm in a Heraeus Sepatech Megafuge 1.0.The pellet is resuspended in 10-20 vol. Hepes buffer (20 mM Hepes, 5 mMMgCl₂, pH 7.1 (KOH)) and homogenized for 10-20 seconds using anUltra-Turrax homogenizer. The homogenate is centrifuged for 30 min at 23000 g. The pellet is resuspended in 5-10 ml Hepes buffer, homogenized5-10 seconds with the Ultra-Turrax and centrifuged for 10 min at 23 000g. Following this centrifugation step, the membrane pellet isresuspended in 2-4 ml Hepes buffer, homogenized with a syringe orteflonhomogenizer, and the protein concentration determined. Themembranes are diluted to a protein concentration of 1-5 mg/ml in Hepesbuffer, aliquoted and kept at −80° C. until use.

Aliquots of the membrane suspension are incubated for 60 min at 25° C.with 30 pM [¹²⁵I]-iodoproxifan, a known compound with high affinity forthe H3 receptor, and the test compound at various concentrations. Theincubation is stopped by dilution with ice-cold medium, followed byrapid filtration through Whatman GF/B filters pretreated for 1 hour with0.5% polyethyleneimine. The radioactivity retained on the filters iscounted using a Cobra II auto gamma counter. The radioactivity of thefilters is indirectly proportional to the binding affinity of the testedcompound. The results are analysed by nonlinear regression analysis.

When tested, the present compounds of the formula (I) generally show ahigh binding affinity to the histamine H3 receptor.

Preferably, the compounds according to the invention have an IC₅₀ valueas determined by one or more of the assays of less than 10 μM, morepreferred of less than 1 μM, and even more preferred of less than 500nM, such as of less than 100 nM.

Functional Assay (I)

The ability of the compounds to interact with the histamine H3 receptoras agonists, inverse agonists and/or antagonists, is determined by an invitro functional assay utilizing membranes from HEK 293 cell expressingthe human H3 receptors.

The H3 receptor is cloned by PCR and subcloned into the pcDNA3expression vector. Cells stably expressing the H3 receptor are generatedby transfecting the H3-expression vectors into HEK 293 cells and usingG418 to select for H3 clones. The human H3-HEK 293 clones are culturedin DMEM with glutamax, 10% foetal calf serum, 1% penicillin/streptavidinand 1 mg/ml G 418 at 37° C. and 5% CO₂.

The H3 receptor expressing cells are washed once with phosphate bufferedsaline (PBS) and harvested using versene (GIBCO-BRL). PBS is added andthe cells are centrifuged for 5 min at 188 g. The cell pellet isresuspended in stimulation buffer to a concentration of 1×10⁶ cells/ml.cAMP accumulation is measured using the Flash Plate® cAMP assay (NEN™Life Science Products). The assay is generally performed as described bythe manufacturer. Briefly, 50 μl cell suspension is added to each wellof the Flashplate which also contained 25 μl 40 μM isoprenaline, tostimulate cAMP generation, and 25 μl of test compound (either agonistsor inverse agonists alone, or agonist and antagonist in combination).The assay can be run in “agonist-mode” which means that the testcompound is added, in increasing concentration, on its own, to thecells, and cAMP is measured. If cAMP goes up, it is an inverse agonist;if cAMP does not change, it is a neutral antagonist, and if cAMP goesdown, it is an agonist. The assay can also be run in the“antagonist-mode” which means that a test compound is added, inincreasing concentrations, together with increasing concentrations of aknown H3 agonist (eg RAMHA). If the compound is an antagonist,increasing concentrations of it cause a right-ward shift in theH3-agonist's dose-response curves. The final volume in each well is 100μl. Test compounds are dissolved in DMSO and diluted in H₂O. The mixtureis shaken for 5 min, and allowed to stand for 25 min at roomtemperature. The reaction is stopped with 100 μl “Detection Mix” perwell. The plates are then sealed with plastic, shaken for 30 min,allowed to stand overnight, and finally the radioactivity is counted inthe Cobra II auto gamma topcounter. EC₅₀ values are calculated bynon-linear regression analysis of dose response curves (6 pointsminimum) using GraphPad Prism. Kb values are calculated by Schild plotanalysis.

The Open Cage Schedule-fed Rat Model

The ability of the present compounds to reduce weight is determinedusing the in vivo open cage Schedule-fed rat model.

Sprague-Dawley (SD) male rats of an age of about 1½ to 2 months and aweight of about 200-250 g are purchased from Mølleg{dot over (a)}rdBreeding and Research Centre A/S (Denmark). On arrival they are allowedsome days of acclimatisation before being placed in individual openplastic cages. They are habituated to the presence of food (Altrominpelleted rat chow) in their home cage only during 7 hours in the morningfrom 07.30 to 14.30 h all days a week. Water is present ad libitum. Asthe consumption of food has stabilised after 7 to 9 days, the animalsare ready for use.

Each animal is used only once to avoid carry-over effects betweentreatments. During the test sessions, the test compound is administeredintraperitoneally or orally 30 min before the start of the sessions. Onegroup of animals is administered the test compound at different dosesand a control group of animals is given a vehicle. Food and water intakeare monitored at 1, 2 and 3 hours post administration.

Any side effects may rapidly be discovered (barrel-rolling, bushy furetc.) since the animals are kept in transparent plastic cages to enablecontinuous monitoring.

The invention described and claimed herein is not to be limited in scopeby the specific embodiments herein disclosed, since these embodimentsare intended as illustrations of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description. Such modifications are alsointended to fall within the scope of the appended claims.

Various references are cited herein, the disclosure of which areincorporated by reference in their entireties.

1. A method for treating overweight or obesity, comprising:administering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of formula (I):

wherein m is 1, R¹ is C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, which mayoptionally be substituted with one or more substituents selected fromhalogen, C₁₋₆-alkoxy and hydroxy, C₃₋₈-cycloalkyl, C₅₋₈-cycloalkenyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, di(C₃₋₈-cycloalkyl)-C₁₋₆-alkyl,C₃₋₈-cycloalkyl-C₂₋₆-alkenyl, C₃₋₈-cycloalkyl-C₂₋₆-alkynyl,C₅₋₈-cycloalkenyl-C₁₋₆-alkyl, C₅₋₈-cycloalkenyl-C₂₋₆-alkenyl,C₅₋₈-cycloalkenyl-C₂₋₆-alkynyl, wherein the cyclic moieties mayoptionally be substituted with one or more substituents selected fromC₁₋₆-alkyl, halogen, trifluoromethyl and 2,2,2-trifluoroethyl, R² isC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl orC₃₋₈-cycloalkyl-C₁₋₆-alkyl, X is —CH₂—(CH₂)_(n)—,—(CH₂)_(n)—CH═CH—(CH₂)_(p)—, —CH₂—(CH₂)_(n)—O—(CH₂)_(p)—,—CH₂—(CH₂)_(n)—C(═O)—(CH₂)_(p)—, —CH₂—(CH₂)_(n)—S—(CH₂)_(p)—,—CH₂—(CH₂)_(n)—S(═O)—(CH₂)_(p)— or —CH₂—(CH₂)_(n)—S(═O)₂—(CH₂)_(p)—, nand p are independently 0, 1, 2, 3 or 4, R³ and R⁴ are independentlyhydrogen, methyl or trifluoromethyl, Y is (a) phenyl, naphthyl, pyridyl,benzoxazolyl or benzothiophenyl, which may optionally be substitutedwith one or more substituents selected from halogen, nitro, cyano,hydroxy, oxo, C₁₋₇-alkanoyl, C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, trifluoromethyl,trifluoromethoxy, —NR⁵R⁶ and —O(C═O)NR⁵R⁶,  wherein R⁵ and R⁶independently are hydrogen, C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₇-alkanoylor aryl, or R⁵ and R⁶ together with the nitrogen atom to which they areattached form a 4 to 7 membered, saturated or unsaturated ring, orwherein two substituents in adjacent positions form a radical—O—(CH₂)₁₋₃—O—, phenyl, phenoxy, phenyl-C₁₋₆-alkyl andphenyl-C₁₋₆-alkoxy, wherein the ring moieties optionally may besubstituted with one or more substituents selected from halogen, nitro,cyano, hydroxy, C₁₋₇-alkanoyl, C₁₋₆-alkylthio, C₁₋₆-alkylsulfonyl,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₈-cycloalkyl, trifluoromethyl,trifluoromethoxy, —NR⁷R⁸ and —O(C═O)NR⁷R⁸,  wherein R⁷ and R⁸independently are hydrogen, C₁₋₆-alkyl, C₃₋₈-cycloalkyl, C₁₋₇-alkanoylor aryl, or R⁷ and R⁸ together with the nitrogen atom to which they areattached form a 4 to 7 membered, saturated or unsaturated ring, orwherein two substituents in adjacent positions form a radical—O—(CH₂)₁₋₃—O— (b) C₃₋₈-cycloalkyl, which may optionally be substitutedwith one or more substituents selected from C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, cyano, trifluoromethyl, trifluoromethoxy and halogen, aswell as any diastereomer or enantiomer or tautomeric form thereof,mixtures of these or a pharmaceutically acceptable salt thereof.
 2. Amethod according to claim 1, wherein the therapeutically effectiveamount of the compound is in the range of from about 0.05 mg to about2000 mg per day.
 3. A method according to claim 1, wherein thetherapeutically effective amount of the compound is in the range of fromabout 0.1 mg to about 1000 mg per day.
 4. A method according to claim 1,wherein the therapeutically effective amount of the compound is in therange of from about 0.5 mg to about 500 mg per day.